AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Sir James Paget first described Paget disease (PD) of the breast in 1874. He reported a chronic eczematous disease on the skin of the nipple and the areola in 15 women, with an associated intraductal carcinoma of the underlying mammary gland. In 1881, Thin illustrated the first histologic description of PD. Crocker described the first case of extramammary PD (skin disorder presenting with clinical findings similar to those in mammary PD) on the glans penis in 1889. In 1901, Dubreuilh reported a case on the vulva.

Mammary PD occurs almost exclusively in women. Involvement of the male breast is rarely reported. Patients with PD frequently present with a chronic, eczematous rash on the nipple and adjacent areolar skin. Proper recognition of this disorder is required to initiate an appropriate workup (eg, skin biopsy) for differentiating it from other benign inflammatory dermatosis and for detecting an underlying breast carcinoma. A similar disease involving the skin of female and male external genitalia (ie, vulva, glans penis) is known as extramammary PD. Histologic features of mammary PD and extramammary PD are similar; however, the histogenesis and the pathogenesis are different.

Pathophysiology

The pathogenesis of mammary PD and the origin of Paget cells were once controversial. It is now widely accepted as an underlying intraductal carcinoma of the breast with retrograde extension into the overlying epidermis through mammary duct epithelium. Malignant epithelial (Paget) cells infiltrate and proliferate in the epidermis, causing thickening of the nipple and the areolar skin. These tumorous epithelial cells are derived from luminal lactiferous ductal epithelium of the breast tissue (see Media File 1). They possess microscopic features of glandular cells. Paget cells and underlying ductal carcinoma cells have been shown to be positive for the oncogene Her-2Neu, suggesting common genetic alterations for both the epidermal and breast tumor cells.

Speculation is that Paget cells may derive from glandular cells and/or epidermal Toker cells (clear cells of the nipple epithelium). In 2001, Kuan et al¹ reported on the immunohistochemical expression of apomucin MUC1, MUC2, and MUC5AC in PD and concluded that both epidermal Paget cells and underlying ductal carcinoma exhibit the same phenotypic apomucins that are also expressed by the Toker cells. In 2003, Morandi et al² reported chromosomal alterations, such as loss of heterozygosity and mitochondrial DNA displacement loop sequence analysis, seen in Paget cells are different from those in underlying breast carcinoma cells. They suggested that the epidermal Paget cells are genetically different from those of breast carcinoma.
 
A concept of a "collision" (coexisting) of neoplastic lesion of mammary PD and underlying carcinoma is therefore presented. However, this study is based on only a few cases. Further studies are necessary to arrive at a more definitive conclusion concerning collision lesions.

Paget cells often express cell markers that mimic those of the underlying breast carcinoma, including glandular epithelial cell markers (ie, low-molecular-weight cytokeratins [CKs], or CAM 5.2). They also express tumor markers, including carcinoembryonic antigen (CEA); Ca 15-3 (milk fat globule protein); some oncogenes (TP53, c-erb B-2) (approximately 85% of cases tested for c-erb B-2 are positive); and other cell markers, such as epithelial membrane antigen (EMA) (all cases tested are EMA positive) and gross cystic disease fluid protein (GCDFP-15) that are found in tumor cells of ductal carcinoma of the breast. Paget cells also share similar immunohistochemical characteristics with eccrine and apocrine sweat gland epithelium. Paget cells are periodic acid-Schiff (PAS) positive and diastase resistant; and they are Alcian blue positive at pH 2.5 in 32% and 18%, respectively.

Advances in immunohistochemistry further define the histogenesis of Paget cells. CK7 has been proposed as a specific and nearly 100% sensitive marker for mammary PD; while CK20 is negative in mammary Paget cells, about 33% of cases of extramammary PD express this marker.

The mechanism by which large neoplastic cells of glandular origin, ie, the Paget cells infiltrate and spread to the overlying epidermal layers of the nipple and adjacent areola is induced by a mobility factor (heregulin-alpha) that acts through the HER2/NEU receptor. Normal epidermal keratinocytes produce and release the mobility factor heregulin-alpha. This factor plays a significant role in the pathogenesis of PD. Paget cells express heregulin receptors HER2/NEU and coreceptors HER3 and HER4. These receptor complexes on Paget cells bind heregulin-alpha, the mobility factor, resulting in the chemotaxis of breast ductal carcinoma cells. This process, in turn, causes migration and infiltration of Paget cells into the overlying epidermis of the nipple and the areolar skin.

Frequency

United States

About 1-4% of female breast carcinoma cases are associated with PD of the nipple, the areola, and the surrounding skin; nearly 100% of mammary PD cases are associated with an underlying carcinoma, either in situ (intraductal, 10%) or infiltrating cancer (90%). Occasional cases of PD have been reported in ectopic breast (1) or supernumerary nipples (2).

International

The exact frequency of mammary PD is unclear.

Mortality/Morbidity

One half (50%) of patients with PD presenting with a palpable breast mass have associated axillary lymph node metastasis. Two thirds of patients with axillary node metastasis were reported to have a palpable breast mass, whereas one third of patients with axillary metastasis did not have a palpable mass. Even in patients with mammary PD and no underlying tumor, 30% may develop an invasive carcinoma at a later date, and 20% of patients already have an associated in situ carcinoma of the breast. However, other reports indicate that no axillary metastases were detected in patients without a palpable breast mass.

• Survival is related to the presence or the absence of a palpable breast tumor. When present, the prognosis is the poorest. About 31 (62%) of 50 patients with mammary PD present with a detectable breast mass.
• Patients with an identifiable associated underlying breast tumor have a survival rate of 38-40% at 5 years and a survival rate of 22-33% at 10 years. The death rate of metastatic breast carcinoma in patients with mammary PD and underlying cancer is 61.3%, with a 10-year cumulative survival rate of 33%.
• The reported survival rate of patients with PD without a palpable breast tumor (prior to surgery) ranges from 92-94% at 5 years and from 82-91% at 10 years.

Race

No racial predisposition is reported.

Sex

Mammary PD occurs almost exclusively in females. PD of the male breast is extremely rare. The estimated occurrence of male breast carcinoma is only 1% of the rate in females. A rare case of PD in the male breast was recorded after treatment of a prostate carcinoma with estrogen.

Age

In female patients with mammary PD, ages range from 24-84 years, with a mean age at diagnosis of 55 years; the average age range is 53-59 years. The average age of patients with mammary PD is 5-10 years older than individuals with breast carcinoma. The age of onset in male patients is generally in the fifth and sixth decades, with a range from 48-80 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Patients with mammary PD present with a relatively long history of an eczematous skin lesion or persistent dermatitis in the nipple and adjacent areas.

• Eczematous skin lesions are associated with several symptoms.
• • Erythema
  • Scaling
  • Itching
  • Burning sensation
  • Ulceration
  • Oozing with serosanguineous discharge
  • Bleeding
  • Some combination of the above symptoms
• Early symptoms and signs of mammary PD
• • Excoriation from itching
  • Resolution and recurrence of small vesicles within the skin lesion
• Symptoms of pain, itching, and a burning sensation prompt patients to seek medical attention.

Physical

• Scaly, erythematous, crusty, and thickened plaques on the nipple, spreading to the surrounding areolar areas, are typical (see Media Files 2-3).
• An erythematous patch in mammary PD is usually sharply demarcated and infiltrated (unlike eczematous dermatitis).
• Retraction of the nipple (see Media File 4) or the presence of palpable nodules indicates an underlying breast cancer.
• Serosanguineous discharge from the nipple may be present.
• Lesion size ranges from 3 mm to 15 cm in diameter; the mean size is 2.8 cm in diameter.
• Nipple invagination is sometimes seen (see Media File 4).
• Nipple changes are associated with an underlying carcinoma of the breast (ie, in situ, infiltrating ductal carcinoma) in more than 98% of patients; as many as two thirds of patients have a palpable breast tumor.
• Unilateral involvement is the rule; however, bilateral mammary PD has occasionally been reported.
• Rare cases of female patients with PD of supernumerary nipples have been reported.³

Causes

Mammary PD is always associated with an underlying carcinoma of the breast. The dermatosis reflects epidermotropism with spread of ductal carcinoma cells through the lactiferous ducts and ductules to the surface epidermis. By thorough histologic examination, Muir documented intraepidermal extension of malignant ductal epithelial cells from underlying breast tissue into the epidermis. The findings are the basis of the epidermotropic theory of mammary PD.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Nipple duct adenoma
Erosive adenomatosis of the nipple (a benign neoplasm of the major nipple ducts)
Malignant melanoma in situ (see Media File 5)
Benign Toker cell (clear cell of the nipple epidermis) hyperplasia

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Imaging Studies

• Radiographic changes seen in mammary PD
• • Subareolar microcalcifications (helpful in evaluating and locating clinically occult, nonpalpable underlying breast carcinoma)
  • Architectural distortion
  • Thickening of the nipple and the areola (reflecting edema)
  • Nipple changes (in a minority of patients)
• About 50-70% of patients with biopsy-proven mammary PD show positive findings on mammography; image-guided biopsy is assisted by positive results on mammography.

Other Tests

• Scrape cytology has been suggested as a noninvasive and reliable, rapid diagnostic screening method for mammary PD.
• • Scrape the affected area of the nipple with a glass slide or a wooden spatula and stain the smears with Papanicolaou or Giemsa stain.
  • The presence of large cells with a high nuclear-to-cytoplasmic ratio, occasional acinar formation, and intracytoplasmic vacuoles is diagnostic for malignant Paget cells.
  • Using histochemical staining methods for the presence of epithelial mucin and immunoperoxidase stains, such as anti-CEA, enhances cytologic results and confirms the diagnosis of mammary PD.
  • Drying artifact on the microscopic slides may produce both false-positive and false-negative results.

Procedures

• Punch, wedge, or excisional biopsy of the lesional skin of the nipple-areola complex to include the dermal and subcutaneous tissue for detailed microscopic examination provides an adequate sample for the accurate diagnosis of mammary PD.

Histologic Findings

Several variants of PD of the breast show identical histopathologic features. The epidermis exhibits hyperkeratosis, parakeratosis, and acanthosis. Infiltration occurs by variable numbers of large, rounded or ovoid, signet-ring forms and sometimes mucin-positive, malignant-appearing tumor cells that are present in all layers of the epidermis. The tumor cells contain abundant pale-staining or sometimes eosinophilic cytoplasm and large vesicular-to-hyperchromatic nuclei with prominent nucleoli (see Media File 6 and Media File 7 [left]). The malignant cells infiltrating the epidermis of the nipple are CK7 positive, exhibiting a typical invasive “shotgun” pattern.  Epidermal keratinocytes are negative for CK7.

Mitotic figures are occasionally identified. The cytoplasm may contain periodic acid-Schiff–positive, diastase-resistant granules, indicating the presence of neutral mucopolysaccharides. Less often, acid mucopolysaccharides (sialomucin) may be identified by Alcian blue reaction at pH 2.5, but not at lower pH 0.4, or aldehyde Fuchsin.

Melaninlike pigment that is dihydroxyphenylalanine (DOPA)–negative is occasionally noted. Paget cells are devoid of intercellular bridges on hematoxylin and eosin (H&E)–stained sections. They often compress the basal keratinocytes that lie between the Paget cells and the papillary dermis.

Paget cells are arranged singly or in a nested pattern, with occasional ductal formations (see Media File 6). Masses of large cells with numerous mitoses are observed in the advancing border of mammary PD. In the ulcerated lesions of mammary PD, the epidermis is totally replaced by Paget cells. Paget cells do not invade the dermis directly; however, they frequently extend along the follicular and sweat gland epithelia.

A large biopsy or excision may demonstrate the presence of epidermal Paget cells and an underlying infiltrating or intraductal carcinoma of the breast. The epidermal involvement by Paget cells is not always immediately adjacent to an underlying breast carcinoma.

The several histologic variants of Paget are as follows:

• Adenocarcinomalike cell type: Cells are columnar similar to an adenocarcinoma metastasizing to the skin.
• Spindle cell type: Tumor cells are angular, elongated, arranged in a nested pattern, and grow in compact masses.
• Anaplastic cell type: Cells resemble those seen in Bowen disease. Pleomorphic tumor cells may be present in a full-thickness, distorted epidermis; a nested pattern is usually not present. Apoptotic (necrotic) tumor cells, mitotic figures, and multinucleated tumor cells are common. Acantholysis with cleft formation are helpful features. The positive immunoperoxidase staining for the presence of markers, such as CEA, EMA, and c-erb B-2, favor a diagnosis of mammary PD and rule against a diagnosis of Bowen disease.
• Acantholytic cell type: This subtype may overlap with the anaplastic variant as described above. Prominent acantholysis may lead to the misinterpretation of mammary PD as an acantholytic disorder involving the skin of the nipple and the areola.
• Pigmented cell type: Rare cases of pigmented mammary PD have been reported.⁴ The pigmented Paget cells are DOPA negative. The melanin pigment is transferred from the melanocytes into the malignant Paget cells. The number of melanocytes is not increased in these lesions.

Tumorous Paget cells are negative for estrogen and progesterone receptor sites, though one half of breast carcinomas are positive for these hormone receptors. In cases of positive estrogen and progesterone receptors in an underlying breast carcinoma, the overlying PD is negative for these receptors. Paget cells are negative for mammary gland markers, such as lysozyme, k-casein, and alpha-lactalbumin.

The dermis contains a dense infiltrate of lymphocytes, histiocytes, plasma cells, and occasionally eosinophils.

Paget cells can be demonstrated by immunohistochemical methods using several antibodies to cell surface and cytoplasmic markers (eg, low-molecular-weight keratins found in simple epithelia, EMA, c-erb B-2, polypclonal pCEA+). These markers are negative in the neighboring keratinocytes; therefore, the markers can be used to reliably distinguish PD from Bowen disease. Paget cells show negative staining by anti-S-100 protein, which serves as a differentiating feature from malignant melanoma in situ. Most Paget cases are positive for CK7 and GCDFP-15.

The ultrastructural features of Paget cells are those of glandular epithelial cells. The pale cytoplasm of Paget cells lacks the dense CK filaments and keratohyalin granules of keratinocytes. Numerous free ribosomes, lysosomes, enlarged mitochondria, prominent smooth and rough endoplasmic reticulum, tonofilaments, Golgi membranes, and microvilli are present on the cell membrane (see Media File 8). Desmosomal attachments between Paget cells and adjacent keratinocytes are fewer and smaller than those between keratinocytes. Paget cells do not directly contact the basal lamina, and no gap junctions or tight junctions are present.

The cytoplasm of Paget cells contains numerous rounded, membrane-bound mucin granules of varying electron density (see Media File 9).

The intraductal carcinoma underlying mammary PD typically shows distended lactiferous ductal lumen by pleomorphic tumor cells with hyperchromatic nuclei, a high nuclear-to-cytoplasmic ratio, and a frequent gland-in-gland (cribriform) pattern (see Media File 10).

Both allergic contact dermatitis and irritant contact dermatitis and fixed drug eruption of the nipple-areola complex show histologic features of an inflammatory dermatosis. No Paget cells are seen in these conditions.

Nipple duct adenoma or erosive adenomatosis of the nipple may mimic mammary PD clinically; however, the histologic features of the former are those of a benign neoplasm of the major nipple ducts. The adenoma cells are negative for c-erb B-2, which is positive in 85% of cases of PD tested.

The following 2 histologic features differentiate Paget cells from melanoma cells:

• Paget cells are situated suprabasally above flattened basal keratinocytes with occasional ductal formation, whereas melanoma cells are located in the basal epidermis and all layers of the epidermis, the so-called intraepidermal pagetoid spread (see Media File 5).
• Paget cells are not present freely in the dermis, whereas melanoma cells are capable of invasion into the dermis. An intraductal or infiltrating ductal carcinoma of the breast can be seen in association with mammary PD.

Immunohistochemistry allows definitive diagnosis of mammary PD.

S-100 protein and homatropine methylbromide (HMB-45) (monoclonal antibody to melanoma cells) are positive in melanoma cells and differentiate melanoma from PD.

CEA is positive in Paget cells and negative in keratinocytes, thus differentiating PD from Bowen disease.

Benign Toker cells are positive for CK7, but negative for CEA and S-100 protein.

Toker (clear) cell hyperplasia of the nipple and the areola is a benign condition without well-defined clinical manifestations. Unlike the Paget cells, the large clear cells do not contain epithelial mucin, and no association with an underlying breast carcinoma exists.

Toker cells may be the origin of intraepithelial Paget cells, based on similarity of immunophenotypes. In cases of florid papillomatosis of the nipple, some CK7-positive cells may be found in the epidermis, a pitfall to be aware of when diagnosing PD of the nipple. Furthermore, the intraepidermal portion of the nipple ducts can be a pitfall for intraepidermal CK7-positive cells. Paget cells differ from melanoma cells by negative cytoplasmic keratin, positive HMB-45, and positive melan-A activity in the latter.

Pagetoid squamous cell carcinoma in situ (Bowen disease) of the breast is rare, and it can be distinguished from PD by negative CK7, positive K903, and positive p16 activity in the former and the reverse result for these antibodies in the latter.

Pseudo-PD may, on occasion, be seen in the major nipple ducts. Large histiocytes infiltrate the epithelium and impart a histologic pattern mimicking PD. The large cells are CK7 negative and strongly positive for CD68.

Staging

Mammary PD has been classified into 4 clinical stages.

• Stage 0 - Lesion confined to the epidermis, without underlying in situ ductal carcinoma of the breast
• Stage 1 - Associated with in situ ductal carcinoma just beneath the nipple
• Stage 2 - Associated with extensive in situ ductal carcinoma
• Stage 3 - Associated with invasive ductal carcinoma

Of all patients with mammary PD, 40-50% have either stage 1 disease or stage 2 disease. These patients have no palpable breast tumor. A palpable breast tumor is a rule in stage 3; more than one half of patients have coexisting axillary lymph node involvement. Patients with breast carcinoma previously treated by local excision and radiation therapy may present with PD of the nipple.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Surgical Care

Mastectomy (radical or modified) and lymph node clearance are appropriate therapies for patients with mammary PD with a palpable mass and underlying invasive breast carcinoma. As many as two thirds of patients are reported to have axillary lymph nodes positive for metastasis. Noninvasive breast carcinoma (in situ carcinoma) is found in about 65% of patients with mammary PD without a palpable mass.

• The number of patients treated by one or more conservative measures (eg, nipple excision and wedge excision of the underlying breast, cone excision, radiation therapy) is small.
• Patients who underwent cone excision and elective tamoxifen therapy had recurrences after an average follow-up of 4.6 years; some developed metastases. Therefore, cone excision is not sufficient therapy for patients with disease limited to the nipple.
• Wide local excision with axillary node sampling is recommended for patients with or without a clinical mass.
• Conservative management includes a combination of local excision of the nipple, wedge resection of the underlying breast, and radiation therapy.
• Radiation therapy alone does not always control occult breast cancer; however, it may be used for patients who refuse mastectomy or those who are medically unfit for surgery.

FOLLOW-UP

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Deterrence/Prevention

• Early dermatologic consultation and a tissue biopsy of the lesion on the nipple and/or the areolar area are necessary for accurate diagnosis of mammary PD.
• Regular mammographic examinations aid in early detection of in situ and invasive breast cancer.

Prognosis

• The prognosis for patients with mammary PD is related to disease stage and appears to be similar to that of women with other types of breast cancer.
• A small number of patients with mammary PD, without a palpable breast mass and with a negative mammogram result, underwent conservative excision of the involved nipple-areola with a wedge resection of the underlying breast tissue and remained disease free at 10-year follow-up.
• Rare cases of recurrent mammary PD have been reported in patients who underwent partial nipple excision; however, no patient developed breast parenchymal recurrence at a mean follow-up of 36 months.
• Of patients with mammary PD (without clinical or mammographic evidence of breast tumor) who were treated with radiation therapy alone or excision plus radiation, 3 of 20 patients developed recurrent disease in the nipple-areola at a mean follow-up of 7.5 years. Those patients eventually underwent a mastectomy.
• According to Osteen,⁵ 9 (11.4%) of 79 patients treated by local excision (with or without radiation therapy) developed recurrences.
• Mastectomy is the standard treatment of mammary PD. Conservative treatment with preservation of the nipple-areola complex results in a higher rate of recurrence than treatment by mastectomy.

Patient Education

• Inform patients that PD of the nipple-areola complex is a rare form of breast cancer that is clinically characterized by eczematous changes in the nipple. Clinical symptoms include erythema, itching, a burning sensation, thickening of the skin, inversion of the nipple, and sometimes a bloody nipple discharge. Usually, symptoms are present for 6 months or more prior to the detection of an underlying breast cancer. A biopsy should promptly be performed on all suspicious lesions of the nipple area for accurate diagnosis and treatment.
• For excellent patient education resources, visit eMedicine's Women's Health Center and Cancer and Tumors Center. Also, see eMedicine's patient education articles Breast Lumps and Pain, Breast Self-Exam, Breast Cancer, and Mastectomy.

MISCELLANEOUS

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to educate patients about the potential for invasive breast carcinoma associated with mammary PD is a pitfall; without this knowledge, patients may delay further diagnostic mammography examination and possibly delay detection of an underlying breast cancer.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Schematic diagram of a female breast depicting the widely accepted concept of pathogenesis of mammary Paget disease. The malignant Paget cells are derived from luminal lactiferous ductal epithelium (A) of the breast tissue with retrograde extension of cancerous Paget cells into the epidermis of the overlying nipple (B). Details are shown in the enlarged circle that reveal thickening of both the lining epithelium of the breast duct and the nipple skin.
	View Full Size Image
Media type:  Image

Media file 2:  A biopsy-proven Paget disease involving the nipple of a 56-year-old woman. She noted the erythematous, swollen, enlarged nipple with focal ulceration and oozing. Occasional serosanguineous discharge and bleeding were present. The patient was later found to have a palpable breast mass and mammography results positive for subareolar microcalcification. No auxiliary lymphadenopathy was found. She was treated by simple mastectomy. At 5-year follow-up, the patient was alive without recurrent or metastatic tumor.
	View Full Size Image
Media type:  Photo

Media file 3:  Clinical photograph of mammary Paget disease affecting a 48-year-old woman. She had experienced a prolonged history of chronic eczematous dermatitis of the nipple and areolar area for several years. The lesion did not respond to topical treatment, and it progressively distorted the nipple with expansion into the surrounding skin. Note a markedly scaly, crusted, and deformed nipple with a thickened, irregularly outlined adjacent nipple-areola complex. An excisional biopsy confirmed the diagnosis of mammary Paget disease. The patient developed an infiltrating ductal carcinoma of the underlying breast tissue with axillary lymph metastasis. She was treated by mastectomy and radiation. No metastatic tumor was noted in the axillary lymph node. She was alive and well 3 years after treatment.
	View Full Size Image
Media type:  Photo

Media file 4:  Nipple invagination, deformed nipple-areola complex, marked erythema, and alternating hyperpigmentation and hypopigmentation noted in the adjacent skin of the breast in a 65-year-old woman with biopsy-proven Paget disease. Note focal scaling of the previous biopsy site. The nipple changes were associated with an intraductal carcinoma of the breast. The patient was treated by conservative excision of the lesion and lumpectomy for the in situ carcinoma. No recurrence or metastatic disease was noted at 6-year follow-up.
	View Full Size Image
Media type:  Photo

Media file 5:  Photomicrograph of a malignant melanoma in situ of the skin displaying prominent intraepidermal pagetoid spread. Note that the melanoma cells are present in all layers of the epidermis, mostly in single units. The cytoplasm of melanoma cells is vacuolated. A moderate upper dermal chronic inflammatory infiltrate is present (hematoxylin and eosin, original magnification X250). S-100 protein and homatropine methylbromide immunostains are positive in the melanoma cells, while carcinoembryonic antigen is negative. No epithelial mucin is seen in these tumor cells.
	View Full Size Image
Media type:  Photo

Media file 6:  A photomicrograph of another lesion of mammary Paget disease. Note the nests of malignant Paget cells predominantly involving the lower layers of the epidermis. The cytoplasm of the tumor cells contains abundant pale staining, granular, mucinous material. Occasional small glandular structures can be seen within the malignant cell nests (hematoxylin and eosin, original magnification X100).
	View Full Size Image
Media type:  Photo

Media file 7:  A composite photomicrograph of mammary PD depicting nests, islands, and individual tumor cells in the epidermis (left, hematoxylin and eosin, original magnification X250). Tumor cells stained positive for carcinoembryonic antigen (CEA) (right, immunostain with anti-CEA, original magnification X250).
	View Full Size Image
Media type:  Photo

Media file 8:  Low-power view of a transmission electron micrograph displaying malignant Paget cells in the lower layer of the epidermis. Note a large Paget cell containing ovoid nucleus (N), scanty nuclear chromatin, a large nucleolus, and abundant pale-staining cytoplasm with smooth and rough endoplasmic reticulum (arrow), scattered enlarged mitochondria, free ribosomes, and lysosomes. No desmosomal attachments are seen between Paget cells and adjacent keratinocytes. Tonofilaments are seen in the keratinocytes (uranyl acetate and lead citrate, original magnification X5,500).
	View Full Size Image
Media type:  Photo

Media file 9:  The cytoplasm of a malignant Paget cell is packed with numerous rounded, membrane-bound mucin granules with various electron densities (uranyl acetate and lead citrate, original magnification X12,000.)
	View Full Size Image
Media type:  Photo

Media file 10:  Photomicrograph of an intraductal carcinoma of the breast underneath Paget disease of the nipple in a 56-year-old woman. Note expansion of the ductal lumen, which is filled with irregularly sized tumor cells of the ductal epithelial origin. Nuclear hyperchromatism and a gland-in-gland (cribriform) pattern are evident. The tumor was detected by a positive mammogram result depicting a focus of microcalcification beneath her nipple.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

1. Kuan SF, Montag AG, Hart J, Krausz T, Recant W. Differential expression of mucin genes in mammary and extramammary Paget's disease. Am J Surg Pathol. Dec 2001;25(12):1469-77. [Medline].
2. Morandi L, Pession A, Marucci GL, Foschini MP, Pruneri G, Viale G, et al. Intraepidermal cells of Paget's carcinoma of the breast can be genetically different from those of the underlying carcinoma. Hum Pathol. Dec 2003;34(12):1321-30. [Medline].
3. Martin VG, Pellettiere EV, Gress D, Miller AW. Paget's disease in an adolescent arising in a supernumerary nipple. J Cutan Pathol. Jun 1994;21(3):283-6. [Medline].
4. Requena L, Sangueza M, Sangueza OP, Kutzner H. Pigmented mammary Paget disease and pigmented epidermotropic metastases from breast carcinoma. Am J Dermatopathol. Jun 2002;24(3):189-98. [Medline].
5. Osteen R. Paget's disease of the nipple. In: Harris J, Hellman S, Henderson JC, eds. Breast Diseases. 2^nd ed. Philadelphia, Pa: JB Lippincott; 1991:797-803.
6. Cabanas RM. An approach for the treatment of penile carcinoma. Cancer. Feb 1977;39(2):456-66. [Medline].
7. Freund H, Maydovnik M, Laufer N, Durst AL. Paget's disease of the breast. J Surg Oncol. 1977;9(1):93-8. [Medline].
8. Kao GF, Graham JH, Helwig EB. Paget's disease of the ectopic breast with an underlying intraductal carcinoma: report of a case. J Cutan Pathol. Feb 1986;13(1):59-66. [Medline].
9. Lewis HM, Ovitz ML, Golitz LE. Erosive adenomatosis of the nipple. Arch Dermatol. Oct 1976;112(10):1427-8. [Medline].
10. Lucarotti ME, Dunn JM, Webb AJ. Scrape cytology in the diagnosis of Paget's disease of the breast. Cytopathology. Oct 1994;5(5):301-5. [Medline].
11. Lundquist K, Kohler S, Rouse RV. Intraepidermal cytokeratin 7 expression is not restricted to Paget cells but is also seen in Toker cells and Merkel cells. Am J Surg Pathol. Feb 1999;23(2):212-9. [Medline].
12. Marucci G, Betts CM, Golouh R, Peterse JL, Foschini MP, Eusebi V. Toker cells are probably precursors of Paget cell carcinoma: a morphological and ultrastructural description. Virchows Arch. Aug 2002;441(2):117-23. [Medline].
13. Meissner K, Rivière A, Haupt G, Löning T. Study of neu-protein expression in mammary Paget's disease with and without underlying breast carcinoma and in extramammary Paget's disease. Am J Pathol. Dec 1990;137(6):1305-9. [Medline].
14. Muir R. Further observation on Paget's disease of the nipple. J Pathol Bacteriol. 1939;49:299.
15. Paone JF, Baker RR. Pathogenesis and treatment of Paget's disease of the breast. Cancer. Aug 1 1981;48(3):825-9. [Medline].
16. Reintgen D, Cruse CW, Wells K, Berman C, Fenske N, Glass F, et al. The orderly progression of melanoma nodal metastases. Ann Surg. Dec 1994;220(6):759-67. [Medline].
17. Sahoo S, Green I, Rosen PP. Bilateral paget disease of the nipple associated with lobular carcinoma in situ. Arch Pathol Lab Med. Jan 2002;126(1):90-2. [Medline].
18. Salama ME, Mahmood MN, Qureshi HS, Ma C, Zarbo RJ, Ormsby AH. p16INK4a expression in actinic keratosis and Bowen's disease. Br J Dermatol. Nov 2003;149(5):1006-12. [Medline].
19. Salvadori B, Fariselli G, Saccozzi R. Analysis of 100 cases of Paget's disease of the breast. Tumori. Sep-Oct 1976;62(5):529-35. [Medline].
20. Salvadori B, Fariselli G, Saccozzi R. Analysis of 100 cases of Paget's disease of the breast. Tumori. Sep-Oct 1976;62(5):529-35. [Medline].
21. Schelfhout VR, Coene ED, Delaey B, Thys S, Page DL, De Potter CR. Pathogenesis of Paget's disease: epidermal heregulin-alpha, motility factor, and the HER receptor family. J Natl Cancer Inst. Apr 19 2000;92(8):622-8. [Medline].
22. Tani EM, Skoog L. Immunocytochemical detection of estrogen receptors in mammary Paget cells. Acta Cytol. Nov-Dec 1988;32(6):825-8. [Medline].
23. Valdes EK, Feldman SM. Paget's disease of the breast. Breast J. Jan-Feb 2006;12(1):83. [Medline].
24. Yao DX, Hoda SA, Chiu A, Ying L, Rosen PP. Intraepidermal cytokeratin 7 immunoreactive cells in the non-neoplastic nipple may represent interepithelial extension of lactiferous duct cells. Histopathology. Mar 2002;40(3):230-6. [Medline].
25. Zeng Z, Melamed J, Symmans PJ, Cangiarella JF, Shapiro RL, Peralta H, et al. Benign proliferative nipple duct lesions frequently contain CAM 5.2 and anti-cytokeratin 7 immunoreactive cells in the overlying epidermis. Am J Surg Pathol. Nov 1999;23(11):1349-55. [Medline].

Article Last Updated: Nov 28, 2007